Fragment screening is used frequently to find new hits for the epigenetic probe project. The SGC has a number of commercial and bespoke fragment libraries aquired through collaborations with Diamond Light Source and the 3D Fragment Consortium. A current project in collaboration with Diamond aims to develop a poised fragment library such that any fragment hit can be rapidly elaborated with parallel chemistry. In conjunction with high throughput crystal soaking (HCS) we hope to dramatically decrease the time from chemical probe hit to lead.
The SGc runs 3 different main screening platforms:
The screening group is integral part of Chemical Biology Program efforts in identifying the selective small molecule ligands for human proteins with these main benefits:
Tight-binding ligands have the potential to stabilize and solubilize proteins, reduce aggregation and thereby enhance crystallization success rates of SGC targets.
Selective small molecule tools can facilitate target validation of proteins for therapeutic intervention, by probing their roles in biochemical processes related to disease.
Activities of the group are focused on:
Assembly and curation of protein family focused compound libraries, driven by literature review, selection and purchase of commercially available compounds, and also augmented by synthesis of new compounds by Med-chem. group.
Hit identification by in-house medium throughput screening of the libraries is combined with collaborations with high-throughput screening groups.
Where possible, de novo design to accelerate hit identification.
Screening of the followup compounds to identify the most appropriate hits for further study and, where necessary, generation of SAR to optimize physicochemical properties.